Our goal is to develop a safe, reversible method of menstrual suppression with antiprogestins, compounds that block progesterone (P) action. For these studies we treated naturally cycling monkeys with the potent antiprogestin, ZK 137 316 (ZK; Schering AG, Berlin) and we have now developed a short-term regimen that will reversibly inhibit menses for 55-60 days. Injection of ZK (0.05 and 0.1 mg/kg body weight) for 40 days significantly extended the intermenstrual interval, blocking frank menstruation (menses detected externally) during the treatment period. Analysis of serum samples for estradiol (E2) and P revealed that in the 0.05 mg ZK group, 3 of the 6 monkeys failed to develop a normal luteal phase and 2 of the 6 monkeys failed to demonstrate an E2 surge, but non-surge E2 levels were normal. Similar results were seen in the 0.1 mg group. ZK treatment suppressed frank menstruation whether or not the luteal phase was normal or blocked. In ovulatory monkeys, minor bleeding, detectable only by vaginal swab, occurred at the time of expected menstruation, suggesting that at these levels of ZK, P withdrawal could only induce minimal endometrial bleeding. The effects of ZK treatment were reversible and all the groups had menstrual cycles with normal patterns of E2 and P by the second post-treatment cycle. We further evaluated the ability of various doses of ZK to antagonize P action during the luteal phase in ovariectomized-artificially cycled monkeys. ZK treatment at 0.01 mg/kg did not sufficiently antagonize P action to induce menses, 0.03 and 0.05 mg/kg induced minor bleeding detectable only by swab, while 0.1 and 0.15 mg/kg reliably induced full menses in all of the monkeys tested. In summary, we have shown that antiprogestin treatment will reversibly inhibit full menstruation in rhesus monkeys and have gathered additional information on appropriate dose levels for further studies of antiprogestin action on endometrial bleeding.